| 1. |
- Elbaz, Alexis, et al.
(författare)
-
Independent and Joint Effects of the MAPT and SNCA Genes in Parkinson Disease
- 2011
-
Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 69:5, s. 778-792
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. Methods: Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. Results: Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 30 end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. Interpretation: This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects. ANN NEUROL 2011; 69: 778-792
|
|
| 2. |
- Antonelli, Alexandre, 1978, et al.
(författare)
-
Conceptual and empirical advances in Neotropical biodiversity research
- 2018
-
Ingår i: PeerJ. - : PeerJ. - 2167-8359. ; 2018:10
-
Tidskriftsartikel (refereegranskat)abstract
- The unparalleled biodiversity found in the American tropics (the Neotropics) has attracted the attention of naturalists for centuries. Despite major advances in recent years in our understanding of the origin and diversification of many Neotropical taxa and biotic regions, many questions remain to be answered. Additional biological and geological data are still needed, as well as methodological advances that are capable of bridging these research fields. In this review, aimed primarily at advanced students and early-career scientists, we introduce the concept of "trans-disciplinary biogeography," which refers to the integration of data from multiple areas of research in biology (e.g., community ecology, phylogeography, systematics, historical biogeography) and Earth and the physical sciences (e.g., geology, climatology, palaeontology), as a means to reconstruct the giant puzzle of Neotropical biodiversity and evolution in space and time. We caution against extrapolating results derived from the study of one or a few taxa to convey general scenarios of Neotropical evolution and landscape formation. We urge more coordination and integration of data and ideas among disciplines, transcending their traditional boundaries, as a basis for advancing tomorrow's ground-breaking research. Our review highlights the great opportunities for studying the Neotropical biota to understand the evolution of life.
|
|
| 3. |
- Benskin, Jonathan, et al.
(författare)
-
Manufacturing Origin of Perfluorooctanoate (PFOA) in Atlantic and Canadian Arctic Seawater
- 2012
-
Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 46:2, s. 677-685
-
Tidskriftsartikel (refereegranskat)abstract
- The extent to which different manufacturing sources and long-range transport pathways contribute to perfluorooctanoate (PFOA) in the world’s oceans, particularly in remote locations, is widely debated. Here, the relative contribution of historic (i.e., electrochemically fluorinated) and contemporary (i.e., telomer) manufacturing sources was assessed for PFOA in various seawater samples by an established isomer profiling technique. The ratios of individual branched PFOA isomers were indistinguishable from those in authentic historic standards in 93% of the samples examined, indicating that marine processes had little influence on isomer profiles, and that isomer profiling is a valid source apportionment tool for seawater. Eastern Atlantic PFOA was largely (83−98%) of historic origin, but this decreased to only 33% close to the Eastern U.S. seaboard. Similarly, PFOA in the Norwegian Sea was near exclusively historic, but the relative contribution decreased to ∼50% near the Baltic Sea. Such observations of contemporary PFOA in coastal source regions coincided with elevated concentrations, suggesting that the continued production and use of PFOA is currently adding to the marine burden of this contaminant. In the Arctic, a spatial trend was observed whereby PFOA in seawater originating from the Atlantic was predominantly historic (up to 99%), whereas water in the Archipelago (i.e., from the Pacific) was predominantly of contemporary origin (as little as 17% historic). These data help to explain reported temporal and spatial trends from Arctic wildlife biomonitoring, and suggest that the dominant PFOA source(s) to the Pacific and Canadian Arctic Archipelago are either (a) from direct emissions of contemporary PFOA via manufacturing or use in Asia, or (b) from atmospheric transport and oxidation of contemporary PFOA-precursors.
|
|
| 4. |
- Benskin, Jonathan P., et al.
(författare)
-
Perfluoroalkyl Acids in the Atlantic and Canadian Arctic Oceans
- 2012
-
Ingår i: Environmental Science and Technology. - : American Chemical Society. - 0013-936X .- 1520-5851. ; 46:11, s. 5815-5823
-
Tidskriftsartikel (refereegranskat)abstract
- We report here on the spatial distribution of C-4, C-6, and C-8 perfluoroalkyl sulfonates, C-6-C-14 perfluoroalkyl carboxylates, and perfluorooctanesulfonamide in the Atlantic and Arctic Oceans, including previously unstudied coastal waters of North and South America, and the Canadian Arctic Archipelago. Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) were typically the dominant perfluoroalkyl acids (PFAAs) in Atlantic water. In the midnorthwest Atlantic/Gulf Stream, sum PFAA concentrations (Sigma PFAAs) were low (77-190 pg/L) but increased rapidly upon crossing into U.S. coastal water (up to 5800 pg/L near Rhode Island). Sigma PFAAs in the northeast Atlantic were highest north of the Canary Islands (280-980 pg/L) and decreased with latitude. In the South Atlantic, concentrations increased near Rio de la Plata (Argentina/Uruguay; 350-540 pg/L Sigma PFAAs), possibly attributable to insecticides containing N-ethyl perfluorooctanesulfonamide, or proximity to Montevideo and Buenos Aires. In all other southern hemisphere locations, Sigma PFAAs were less than210 pg/L. PFOA/PFOS ratios were typically greater than= 1 in the northern hemisphere, similar to 1 near the equator, and less than= 1 in the southern hemisphere. In the Canadian Arctic, Sigma PFAAs ranged from 40 to 250 pg/L, with perfluoroheptanoate, PFOA, and PFOS among the PFAAs detected at the highest concentrations. PFOA/PFOS ratios (typically greater thangreater than1) decreased from Baffin Bay to the Amundsen Gulf; possibly attributable to increased atmospheric inputs. These data help validate global emissions models and contribute to understanding of long-range transport pathways and sources of PFAAs to remote regions.
|
|
| 5. |
- Calió, Maria Fernanda, et al.
(författare)
-
Spatio-temporal evolution of the catuaba clade in the Neotropics: Morphological shifts correlate with habitat transitions
- 2022
-
Ingår i: Journal of Biogeography. - : Wiley. - 0305-0270 .- 1365-2699. ; 49:6, s. 1086-1098
-
Tidskriftsartikel (refereegranskat)abstract
- Aim The biotic assembly of one of the most species-rich savannas, the Brazilian Cerrado, has involved recruitment of lineages from several surrounding regions. However, we lack a clear understanding about the timing and pathways of biotic exchanges among these regions and about the role those interchanges had in the assembly of Neotropical biodiversity. We investigated the timing and routes of species movements between wet or seasonally dry habitats across Neotropical regions and assessed the potential for ecological adaptation by evaluating the habitat transitions correlated with morphological shifts. Location Neotropics. Taxon The plant genus Anemopaegma (Bignonieae, Bignoniaceae). Methods We inferred a Bayesian molecular phylogeny of Anemopaegma using one nuclear and two chloroplast markers. We sampled more than 90% of the known species diversity of Anemopaegma, covering its full geographical range. We estimated divergence times using a Bayesian relaxed-clock approach and inferred ancestral ranges as well as shifts in habitat and morphological characters. Results Phylogenetic analyses recovered seven main clades within Anemopaegma. The genus likely originated in Amazonia in the late Oligocene. Early-diverging lineages diversified in situ in Amazonia, particularly during the Miocene, with independent dispersal events to the Andes, Atlantic Forest and Cerrado. Shifts from seasonally dry forest to savanna habitats were correlated with shifts from liana to shrub and the loss of tendrils. Main Conclusions The timing of diversification of major lineages within Anemopaegma is consistent with major geological and climatic events that occurred during the late Palaeogene and Neogene, such as the Andean uplift and the Middle Miocene Climatic Optimum. Movements across different regions within the Neotropics were relatively common but shifts between habitats were not. The correlation in the evolution of the shrubby habit, the loss of tendrils and the shifts from forest to savanna are consistent with a scenario of ecological adaptation.
|
|
| 6. |
- Dreier, J. P., et al.
(författare)
-
Migraine and delayed ischaemic neurological deficit after subarachnoid haemorrhage in women: a case-control study
- 2007
-
Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101. ; 14:12, s. 1363-1368
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of the present case-control study was to investigate the role of migraine as a potential risk factor for a delayed ischaemic neurological deficit (DIND) after subarachnoid haemorrhage (SAH). A telephone interview was performed in patients or their relatives to determine the prevalence of migraine. Thirty-six women aged < 60 years had SAH with Hunt & Hess grade I-III and DIND (group A). This group was compared with an age-matched group of 36 female SAH patients, Hunt & Hess grade I-III without DIND (group B). The two populations were also characterized regarding hypertension, smoking, diabetes mellitus and alcohol use. A significant difference was only found for the prevalence of migraine with 47% in group A and 25% in group B (P < 0.05; odds ratio: 2.68, confidence interval: 0.99-7.29). Migraineurs revealed similar prevalences of risk factors independently of the presence of DINDs. This retrospective study suggests that women with migraine have a higher risk to develop a DIND than women without migraine.
|
|
| 7. |
- Hüffmeier, Ulrike, et al.
(författare)
-
Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 996-999
-
Tidskriftsartikel (refereegranskat)abstract
- Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10⁻¹⁷). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10⁻³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10⁻²⁰, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.
|
|
| 8. |
- Keller, Annika, et al.
(författare)
-
Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:9, s. 1077-
-
Tidskriftsartikel (refereegranskat)abstract
- Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait ( idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor beta (PDGF-R beta) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-R beta. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.
|
|
| 9. |
- Klingenberg, Roland, et al.
(författare)
-
Depletion of FOXP3(+) regulatory T cells promotes hypercholesterolemia and atherosclerosis
- 2013
-
Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 123:3, s. 1323-1334
-
Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3(+) Tregs. Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3(+) Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3(+) Tregs inhibit atherosclerosis by modulating lipoprotein metabolism.
|
|
| 10. |
- Stein, Sokrates, et al.
(författare)
-
ApoE-/- PGC-1α-/- mice display reduced IL-18 levels and do not develop enhanced atherosclerosis.
- 2010
-
Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:10
-
Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is a chronic inflammatory disease that evolves from the interaction of activated endothelial cells, macrophages, lymphocytes and modified lipoproteins (LDLs). In the last years many molecules with crucial metabolic functions have been shown to prevent important steps in the progression of atherogenesis, including peroxisome proliferator activated receptors (PPARs) and the class III histone deacetylase (HDAC) SIRT1. The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1. The aim of this study was to analyze total PGC-1α deficiency in an atherosclerotic mouse model.
|
|
| 11. |
- Stein, Stein, et al.
(författare)
-
SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis.
- 2010
-
Ingår i: European heart journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 31:18, s. 2301-2309
-
Tidskriftsartikel (refereegranskat)abstract
- Aims Endothelial activation, macrophage infiltration, and foam cell formation are pivotal steps in atherogenesis. Our aim in this study was to analyse the role of SIRT1, a class III deacetylase with important metabolic functions, in plaque macrophages and atherogenesis. Methods and results Using partial SIRT1 deletion in atherosclerotic mice, we demonstrate that SIRT1 protects against atherosclerosis by reducing macrophage foam cell formation. Peritoneal macrophages from heterozygous SIRT1 mice accumulate more oxidized low-density lipoprotein (oxLDL), thereby promoting foam cell formation. Bone marrow-restricted SIRT1 deletion confirmed that SIRT1 function in macrophages is sufficient to decrease atherogenesis. Moreover, we show that SIRT1 reduces the uptake of oxLDL by diminishing the expression of lectin-like oxLDL receptor-1 (Lox-1) via suppression of the NF-κB signalling pathway. Conclusion Our findings demonstrate protective effects of SIRT1 in atherogenesis and suggest pharmacological SIRT1 activation as a novel anti-atherosclerotic strategy by reducing macrophage foam cell formation.
|
|
| 12. |
- von Lukowicz, Tobias, et al.
(författare)
-
PARP1 is required for adhesion molecule expression in atherogenesis.
- 2008
-
Ingår i: Cardiovascular research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 78:1, s. 158-66
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: Atherosclerosis is the leading cause of death in Western societies and a chronic inflammatory disease. However, the key mediators linking recruitment of inflammatory cells to atherogenesis remain poorly defined. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme, which plays a role in acute inflammatory diseases. METHODS AND RESULTS: In order to test the role of PARP in atherogenesis, we applied chronic pharmacological PARP inhibition or genetic PARP1 deletion in atherosclerosis-prone apolipoprotein E-deficient mice and measured plaque formation, adhesion molecules, and features of plaque vulnerability. After 12 weeks of high-cholesterol diet, plaque formation in male apolipoprotein E-deficient mice was decreased by chronic inhibition of enzymatic PARP activity or genetic deletion of PARP1 by 46 or 51%, respectively (P < 0.05, n >or= 9). PARP inhibition or PARP1 deletion reduced PARP activity and diminished expression of inducible nitric oxide synthase, vascular cell adhesion molecule-1, and P- and E-selectin. Furthermore, chronic PARP inhibition reduced plaque macrophage (CD68) and T-cell infiltration (CD3), increased fibrous cap thickness, and decreased necrotic core size and cell death (P < 0.05, n >or= 6). CONCLUSION: Our data provide pharmacological and genetic evidence that endogenous PARP1 is required for atherogenesis in vivo by increasing adhesion molecules with endothelial activation, enhancing inflammation, and inducing features of plaque vulnerability. Thus, inhibition of PARP1 may represent a promising therapeutic target in atherosclerosis.
|
|
| 13. |
- Wittke, Christina, et al.
(författare)
-
Genotype–Phenotype Relations for the Atypical Parkinsonism Genes : MDSGene Systematic Review
- 2021
-
Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:7, s. 1499-1510
-
Forskningsöversikt (refereegranskat)abstract
- This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated (“bagged”) decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95%CI, 86.3%–86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze palsy, autonomic symptoms, other nonmotor symptoms, levodopa response quantification, and cognitive decline. Comparing monogenic atypical with monogenic typical parkinsonism using 2063 data sets from Movement Disorder Society Genetic mutation database on patients with SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1 mutations, the age at onset was earlier in monogenic atypical parkinsonism (24 vs 40 years; P = 1.2647 × 10−12) and levodopa response less favorable than in patients with monogenic typical presentations (49% vs 93%). In addition, we compared monogenic to nonmonogenic atypical parkinsonism using data from 362 patients with progressive supranuclear gaze palsy, corticobasal degeneration, multiple system atrophy, or frontotemporal lobar degeneration. Although these conditions share many clinical features with the monogenic atypical forms, they can typically be distinguished based on their later median age at onset (64 years; IQR, 57–70 years). In conclusion, age at onset, presence of specific signs, and degree of levodopa response inform differential diagnostic considerations and genetic testing indications in atypical forms of parkinsonism.
|
|
